Claisen Condensation(ngưng tụ claisen)

Acetoacetic-Ester Condensation

Claisen Condensation

Summary

• The Claisen condensation is the ester analogue of the Aldol condensation.
• Reagents : most commonly the base would be the alkoxide, R'O^-
• The reaction involves an ester enolate reacting with another molecule of the ester.
• Remember enolates are good nucleophiles and the ester carbonyl C are electrophilic.
• The products of these reactions are b-ketoesters which are important, useful synthetic intermediates.
• Note that the product is the original ester with an acyl group added i.e. an acylation reaction has occurred.
• A simple example of a Claisen condensation is the reaction of ethyl ethanoate which is shown below in two representations:

The Claisen Condensation between esters containing α-hydrogens, promoted by a base such as sodium ethoxide, affords β-ketoesters. The driving force is the formation of the stabilized anion of the β-keto ester. If two different esters are used, an essentially statistical mixture of all four products is generally obtained, and the preparation does not have high synthetic utility.

However, if one of the ester partners has enolizable α-hydrogens and the other does not (e.g., aromatic esters or carbonates), the mixed reaction (or crossed Claisen) can be synthetically useful. If ketones or nitriles are used as the donor in this condensation reaction, a β-diketone or a β-ketonitrile is obtained, respectively.

The use of stronger bases, e.g. sodium amide or sodium hydride instead of sodium ethoxide, often increases the yield.

The intramolecular version is known as DieckmannCondensation

Translate to Vietnamese:

 Hiểu sơ bộ:

• Là phản ứng giữa 2 ester có α-hydrogen
• Xúc tác: base như EtONa, MeONa,NaNH2,NaH
• Tạo ra sản phẩm trung gian ổn định: anion của β-keto ester
• Sản phẩm tạo ra là β-keto ester
• Khi 2 ester là khác nhau: tạo ra một hỗn hợp 4 sản phẩm β-keto ester

Mechanism of the Claisen Condensation

Example

1.

claisen condensation 

General, Robust, and Stereocomplementary Preparation of α,β-Disubstituted α,β-Unsaturated Esters
H. Nakatsuji, H. Nishikado, K. Ueno, Y. Tanabe, Org. Lett., 2009, 11, 4258-4261.

Translate to Vietnamese:

• NEt3(TEA): Triethylamin, là xúc tác base
• TiCl4: vai trò phản ứng với EtOH tạo ra, thúc đẩy phản ứng xảy ra theo chiều thuận.
  TiCl4 + 4EtOH -----------------> Ti(OC2H5)4 + 4 HCl
• Dung môi CH2Cl2 hoặc toluen: Phải dùng dung môi hòa tan cả 2 chất phản ứng, tạo nên hệ đồng thể thì hiệu suất mới cao( nói đúng hơn phản ứng mới xảy ra)

2.

 Abstract

Thioesters undergo chemoselective soft enolization and acylation by N-acylbenzotriazoles on treatment with MgBr₂·OEt₂ and i -Pr₂NEt to give β-keto thioesters without prior enolate formation. The reaction is conducted using untreated CH₂Cl₂ open to the air. The coupled products can be converted directly into β-keto esters, β-keto amides, and β-diketones under mild conditions.

Direct Carbon-Carbon Bond Formation via Chemoselective Soft Enolization of Thioesters: A Remarkably Simple and Versatile Crossed-Claisen Reaction Applied to the Synthesis of LY294002

G. Zhou, D. Lim, D. M. Coltart, Org. Lett., 2008, 10, 3809-3812.

Translate to Vietnamese:

MgBr₂·OEt₂ and i -Pr₂NEt có vai trò: tránh tạo ra enolate.

3.

Mild and Efficient Pentafluorophenylammonium Triflate (PFPAT)-Catalyzed C-Acylations of Enol Silyl Ethers or Ketene Silyl (Thio)Acetals with Acid Chlorides
A. Iida, J. Osada, R. Nagase, T. Misaki, Y. Tanabe, Org. Lett., 2007, 9, 1859-1862.

Powerful Ti-Crossed Claisen Condensation between Ketene Silyl Acetals or Thioacetals and Acid Chlorides or Acids
A. Iida, S. Nakazawa, T. Okabayashi, A. Horii, T. Misako, Y. Tanabe, Org. Lett., 2006, 8, 5215-5218.

Synthesis of Trifluoromethyl Ketones via Tandem Claisen Condensation and Retro-Claisen C-C Bond-Cleavage Reaction
D. Yang, Y. Zhou, N. Xue, J. Qu, J. Org. Chem., 2013, 78, 4171-4176.

Consecutive Michael-Claisen Process for Cyclohexane-1,3-dione Derivative (CDD) Synthesis from Unsubstituted and Substituted Acetone
D. Sharma, Bandna, A. K. Shil, B. Singh, P. Das, Synlett, 2012, 23, 1199-1204.

"One-Pot" Synthesis of 4-Substituted 1,5-Diaryl-1H-pyrazole-3-carboxylic Acids via a MeONa/LiCl-Mediated Sterically Hindered Claisen Condensation-Knorr Reaction-Hydrolysis Sequence
J.-A. Jiang, C.-Y. Du, C.-H. Gu, Y.-F. Ji, Synlett, 2012, 23, 2965-2968.